Differential metabolic effects of novel cilostamide analogs, methyl carbostiryl derivatives, on mouse and hyperglycemic rat

Objective(s): PDE3 has a functional role in Insulin secretion and action. We investigated the metabolic effects of new synthetic PDE3 inhibitors (mc1, mc2, mc5 and mc6), on mice and hyperglycemic rat.

Materials and methods: The test compound or solvent was injected subcutaneously to mice, for 7 days. On day 8, blood and liver samples were obtained. In hyperglycemic rat, 0.5 g/kg glucose with or without test compounds was injected, and followed with infusion of 1.5 g/kg/hr glucose. Blood samples were collected in mentioned intervals and liver was dissected.

Results: In hyperglycemic rat, all test compounds decreased blood glucose and the effect of milrinone was potentiated by glybenclamide. Milrinone or IBMX did not change plasma Insulin levels, but it was augmented by combination of milrinone and glybenclamide. In both species, liver glycogen storage was decreased by IBMX, mc5, mc6 or MCPIP, increased by mc2 (liver glycogen, rat, control=56±2, mc2=70±3 P< 0.01, mice, control=33±0.7, mc2=42±2.3 P< 0.01) and was not changed in the presence of mc1. Milrinone did not change the glycogen storage in rats though increased it in mice (control= 33±0.7, milrinone= 40±1 P< 0.05).

Conclusion: Increasing plasma Insulin levels by combination of milrinone and glybenclamide confirmed that in hyperglycemic rat, the hypoglycemic effect was correlated with increasing Insulin secretion. Variations of plasma Insulin were obscured by the pulsative characteristic of pancreatic Insulin release. Decreasing glycogen storage reflected inhibition of liver PDE activity. The reasons for ineffectiveness of mc1, anabolic effect of mc2, and differential effects of milrinone were not clear.